A progressive sequence of somatic mutations and epigenetic changes of oncogenes or tumor suppressor genes in one single cell are believed to cause tumor development. This initial cell proliferates and due to genomic instability, the cells accumulate genomic changes which lead to clonal expansion and tumor development (Hanahan and Weinberg, Cell 100:57-70, 2000). These genomic changes are irreversible and specific to tumor cells. Therefore, they provide ideal targets for the development of new therapies. However, high genomic instability in tumors causes the accumulation of genomic aberrations that do not contribute do tumor progression. In addition, cancer is a very heterogeneous disease because changes in many different cellular pathways can lead to tumor development. Therefore, it is important to distinguish between ‘driver’ mutations which are functionally important and ‘passenger’ mutations which do not provide a selective advantage to the tumor cells.
Hepatocellular carcinoma (HCC) is the most frequent malignant tumor in the liver and the third leading cause of cancer death worldwide (Parkin et al., CA Cancer J. Clin. 55:74-108, 2005). Various etiologies have been shown to underlie HCC development, including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, chronic alcohol consumption, ingestion of aflatoxin B1 contaminated food as well as inherited hemochromatosis (Farazi and DePinho, Nat. Rev. Cancer 6:674-687, 2006). Surgical resection is the only curative treatment of HCC, but eligibility is sparse because most patients present with advanced disease (McCormack et al., Eur. J. Gastroenterol. Hepatol. 17:497-503, 2005). Systemic chemotherapy has been shown to be ineffective and tumor recurrence rate after surgical resection is high due to relapse and metastasis (Llovet et al., Semin. Liver Dis. 25:181-200, 2005). Therefore, the development of new drugs will be crucial to prevent relapse and to prolong patient survival.
In addition, despite considerable progress during the last few years, the molecular mechanisms and signaling pathways underlying HCC development and progression are still poorly understood. This is likely because HCC, like most other solid tumors, is very heterogeneous in terms of clinical presentation and gene expression patterns.